The discovery and use of antibiotics is considered to be one of the most important breakthroughs in modern medicine, and plays an extremely important role in safeguarding human health and prolonging human life. However, with the widespread use and even abuse of antibiotics in medicine, agriculture, aquaculture, etc., the problem of bacterial resistance has become one of the most pressing major threats to human health in the past two decades. In the past decade, the lag in the development of new antibacterial drugs and the reduction in investment in research and development of new antibacterial drugs by large pharmaceutical companies have exacerbated the severity of the “antibiotic crisis”. In 2014, the World Health Organization pointed out that the world is going towards the “post-antibiotic era”. If the problem of serious lack of effective antibiotics is not effectively alleviated as soon as possible, there may be a terrible possibility that people will die from common infections once again. At present, the main Gram-positive and negative bacteria have been generally resistant to existing antibiotics. Gram-positive bacteria are mainly methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE). Among them, MRSA and VRE are the most harmful. For multidrug-resistant positive bacteria infections, there are still a few drugs such as linezolid, tigecycline, glycopeptides (vancomycin and teicoplanin), so Gram-positive bacteria resistance is still a controllable crisis. The resistance of Gram-negative bacteria is more serious than that of Gram-positive bacteria. Except for the increasing community-acquired multidrug resistant (MDR) Gram-negative bacteria such as Escherichia coli and Neisseria gonorrhoeae, hospital-acquired extensive drug resistant (XDR) and total drug resistant (TDR) Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae are extremely refractory and almost no drug is available, resulting in high mortality of hospital-acquired XDR and TDR infections. Therefore, Gram-negative bacterial resistance is a crisis that has been out of control. It can be seen that the development of drugs that are effective against drug-resistant Gram-negative bacteria is a significant and imminent scientific task for scientists. The resistance mechanisms of Gram-negative bacteria are more complicated than those of Gram-positive bacteria, including bacteria producing β-lactam hydrolase; the expression of the efflux pump pumping the drug out of the bacteria; the mutation of the membrane pore protein leading to the decrease of permeability; the mutations in binding sites and lateral transfer of drug resistance genes. A drug that can treat a drug-resistant negative bacterial infection should have the following characteristics: 1) it can pass through an outer membrane of the negative bacteria; 2) it is not recognized by the efflux pump and is not excreted out of the bacteria; and 3) it is not hydrolyzed by various hydrolases before reaching the target. Therefore, it is very difficult to develop drugs for multidrug-resistant negative bacteria. At present, no substantial progress has been made worldwide, and the drug candidates in clinical research are new structural derivatives of existing class antibiotics such as CAX101, Avibactam (NXL-104), Plazomicin (ACHN-490) and Eravacycline (TP-434). Looking for a new compound that can enter the bacteria with a new mechanism and overcome the mechanisms of bacterial efflux pump and membrane pore protein mutation is the most important direction for the development of new anti-multidrug resistance drug.
Free iron is almost a nutrient for all microorganisms, but it is extremely low in human plasma and body fluids, only 10−9 M, which is much lower than the needs of bacterial colonization and growth. In order to survive and maintain infectious toxicity, bacteria secrete various siderophores (molecules that can efficiently complex iron) to take iron from the host, transport the siderophore into the bacterial cells and release iron through the corresponding siderophore receptor on the outer membrane of the bacteria. Based on the principle of iron uptake of bacteria, the organic combination of the antibacterial drug and the siderophore in an ingenious way makes bacteria actively transport the antibiotics and iron together into the body while taking iron, which will effectively overcome the difficulty of pass through the outer membrane of Gram-negative bacteria and kill the bacteria quickly.

Efforts to design new antibiotics based on the principle of iron uptake of bacteria began in the late 1980s. In 1985, the compound Pirazmonam reported by Bristol-Myers Squibb is better in vitro and in vivo activities against Enterobacter, Pseudomonas aeruginosa and Acinetobacter baumannii than the similar aztreonam and ceftazidime. In 2007, Basilea reported the first siderophore antibiotic, BAL30072, which entered the clinical study. The compound has good antibacterial activity against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, but has less activity against the resistant Gram-negative bacteria that produce cephalosporinase (AmpC) or Class A or Class D extended-spectrum lactamases (ESBLs). At present, the treatment of drug-resistant Gram-negative bacteria infection with BAL30072 and meropenem in combination is in phase I clinical stage. Pfizer reported the Pirazmonam analogue MC-1 in 2011. MC-1 has a MIC90 of 0.5 μg/mL for multidrug-resistant Pseudomonas aeruginosa, a MIC90 of 2 μg/mL for Escherichia coli, and a MIC90 of 8 μg/mL for Klebsiella pneumoniae. Unfortunately, MC-1 is essentially ineffective against Acinetobacter with a MIC90 greater than 64 μg/mL. In addition, MC-1 is chemically unstable and is susceptible to hydrolysis, which limits its further research. In 2012 to 2013, Pfizer reported compounds 4 and 5 in which a hydroxypyridone structure is introduced at the 2-position of the β-lactam ring. The compounds have good activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. But the activity against Acinetobacter baumannii is still low (MIC90>64 μg/mL).
In summary, the monocyclic β-lactam-siderophore conjugates are currently in the preclinical research stage, and only a few individual compounds such as BAL30072 are in the early stages of clinical research. The existing monocyclic β-lactam-siderophore conjugates have obvious deficiencies, and ubiquitously (such as the representative compound BAL30072) the antibacterial activity is not strong, and the antibacterial spectrum is not broad enough to cover the four most important multidrug-resistant Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. In particular, they have no antibacterial activity against important Klebsiella pneumoniae [Antimicrob. Agents Chemother. 2010, 54, 2291-2302], which is a major obstacle to the clinical application of such compounds.
In view of the above problems, the present invention provides a novel monocyclic β-lactam-siderophore conjugate having a novel structure, a stronger antibacterial activity and a broader antibacterial spectrum. The structure of such conjugate is characterized by introducing a substituent at the alpha position of the oxime ether for the first time. The introduction of the substituent makes the compound of the present invention have stronger activity against Gram-negative bacteria, and more importantly, the compounds of the present invention have a broader antibacterial spectrum, and have strong activity against the four most important multidrug resistant Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. 